Dental pulp is soft connective tissue in the central core of a tooth, and maintains homeostasis of the tooth as a biologically viable organ. When caries or trauma involves dental pulp, endodontic therapies are indicated. In irreversible pulpitis, the dentist or endodontist extirpates dental pulp, and obturates the instrumented root canal with bioinert materials. A total of approximately 16 million endodontic procedures are performed each year in the United States alone, with an annual total expenditure of approximately $15 to $25 billion dollars. Whereas root canal therapy is considered one of the successful dental treatments, complications have been repeatedly documented in the literature. Secondary infections due to coronal leakage or undetected accessory root canals are not uncommon, and cause additional distress to both patients and dentists. A substantial amount of tooth structure is removed during root canal treatment, leading to increased incidences of tooth fracture. Root canal treated teeth are devoid of innervation and pulpal sensation, and thus are deprived of the ability to detect secondary infections. In deciduous teeth or young permanent teeth with incomplete root apex formation, endodontic treatment is either contra-indicated or may lead to the cessation of root development. Scientifically, these complications may be attributed to the end result of the current root canal treatment leading to a devitalized tooth that has lost the mechanisms for homeostasis and host defense of a native tooth. Our preliminary data demonstrate that endodontically treated human teeth are recellularized and revascularized in vivo upon cytokine- induced cell homing approaches following in vivo ectopic implantation of the entire human teeth in mice. These findings provide the proof of concept that dental pulp of endodontically treated human tooth may be revascularized and recellularized orthotopically in vivo. Accordingly, our overall hypothesis is that various elements of dental pulp, including the angiogenic, odontoblastic and neuronal, can be regenerated by cytokine-induced cell homing. The overall goal of this 6-month SBIR/Phase-I proposal is to prepare formulations of singular and combinatory cytokines in biocompatible material scaffolds towards dental pulp regeneration. Our long-term goal is twofold: 1) to determine the efficacy and safety of biologically based dental pulp regeneration in small and large animal models, and 2) to perform randomized and controlled, multi-center clinical trials in endodontic patients, and determine the efficacy and safety of biologically based endodontic therapies. We envision that biologically based therapies will regenerate dental pulp in endodontic patients. PUBLIC HEALTH RELEVANCE: This SBIR/Phase I project will develop prototypes for bioengineered therapies for the regeneration of dental pulp resulting from infection or trauma. A total of approximately 16 million endodontic procedures are performed each year in the United States alone. Current root canal therapy has complications such as secondary infections, post-operative tooth fracture, and a lack of efficacy in deciduous teeth or young permanent teeth. Our preliminary data demonstrate that endodontically treated human teeth are recellularized and revascularized in vivo. We have designed interdisciplinary approaches with a strong potential to regenerate dental pulp in human teeth.